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Duplications of <jats:italic>MECP2<\/jats:italic>-containing genomic segments lead to severe autistic symptoms in human. <jats:italic>MECP2<\/jats:italic>-coding protein methyl-CpG-binding protein 2 (MeCP2) is involved in transcription regulation, microRNA processing and mRNA splicing. However, molecular mechanisms underlying the involvement of MeCP2 in mRNA splicing in neurons remain largely elusive. In this work we found that the majority of MeCP2-associated proteins are involved in mRNA splicing using mass spectrometry analysis with multiple samples from <jats:italic>Mecp2<\/jats:italic>-null rat brain, mouse primary neuron and human cell lines. We further showed that <jats:italic>Mecp2<\/jats:italic> knockdown in cultured cortical neurons led to widespread alternations of mRNA alternative splicing. Analysis of ChIP-seq datasets indicated that MeCP2-regulated exons display specific epigenetic signatures, with DNA modification 5-hydroxymethylcytosine (5hmC) and histone modification H3K4me3 are enriched in down-regulated exons, while the H3K36me3 signature is enriched in exons up-regulated in <jats:italic>Mecp2<\/jats:italic>-knockdown neurons comparing to un-affected neurons. Functional analysis reveals that genes containing MeCP2-regulated exons are mainly involved in synaptic functions and mRNA splicing. These results suggested that MeCP2 regulated mRNA splicing through interacting with 5hmC and epigenetic changes in histone markers, and provide functional insights of MeCP2-mediated mRNA splicing in the nervous system.<\/jats:p>","DOI":"10.1038\/srep42790","type":"journal-article","created":{"date-parts":[[2017,2,17]],"date-time":"2017-02-17T10:15:42Z","timestamp":1487326542000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Regulation of mRNA splicing by MeCP2 via epigenetic modifications in the brain"],"prefix":"10.1038","volume":"7","author":[{"given":"Tian-Lin","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huida","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujian","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,17]]},"reference":[{"key":"BFsrep42790_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","volume":"23","author":"RE Amir","year":"1999","unstructured":"Amir, R. 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